Transdermal drug delivery device

ABSTRACT

A diffusional drug delivery device is described which can provide for stability of the adhesive and system components, elimination of the initial burst of drug and hence irritation, and to provide for delayed onset of therapeutic effect along with delivery of a therapeutic agent at an optimum rate. The therapeutic agent in a first form which is suitable for storage, and the anhydrous activating means are inert when in an anhydrous environment. Moisture activates the system whereby the activating means provides an acidic or basic solution and the first form of the therapeutic agent is converted to a second form which is suitable for absorption through the skin or mucosa.

This application is a continuation of application Ser. No. 118,577,filed Nov. 9, 1987, and now U.S. Pat. No. 4,799,613.

FIELD OF THE INVENTION

This invention relates to the transdermal delivery of drugs or otherbiologically active agents and particularly to novel methods andcompositions for providing stable systems under storage conditions.Still more particularly, this invention relates to novel methods andcompositions for delaying the onset of drug delivery for transdermalsystems.

RELATED PATENT APPLICATIONS

This application is related to the copending, coassigned patentapplication Ser. No. 07/022,301, filed Mar. 5, 1987 entitled "MoistureActivation of Transdermal Drug Delivery System", now abandoned which inturn is a continuation of patent application Ser. No. 06/874,263 nowabandoned, filed June 13, 1986, of the same title; and to the copendingcoassigned patent application, Attorney Docket No. 1543 entitled"Improved Transdermal Drug Delivery Device".

BACKGROUND OF THE INVENTION

The transdermal route of parenteral delivery of drugs provides manyadvantages and transdermal systems for delivering a wide variety ofdrugs or other beneficial agents are described in U.S. Pat. Nos.3,598,122, 3,598,123, 4,286,592, 4,314,577, 4,379,454 and 4,568,343 forexample, all of which are incorporated herein by reference.

In these devices, a drug or other active agent is released by diffusionfrom a reservoir through the agent releasing surface of the device tothe biological environment at which the device is applied. Such devicesperform well in the administration of many agents but are not suitablefor the administration of an agent whose dosage regime requires that theonset of therapeutic effect be delayed for a significant period of timeafter application of the device at the site of delivery. This is becausethe concentration of the therapeutic agent at the surface through whichthe agent is released, at the time of application, is typically at orabove saturation and is capable of delivering at a rate that can giverise to therapeutic blood levels. In some cases, the initial rate ofrelease is unacceptably high and a method for reducing the initial"burst" of agent delivery is described in U.S. Pat. No. 3,923,939 toBaker et al. Even in this patent, the agent releasing surface of thediffusional embodiment does contain agent and delivery commencesimmediately in the manner described above.

Non-diffusional devices are known which do not immediately present drugto the biological environment when installed, such as devices whichcontain material in breakable microcapsules, or fluid imbibing pumps,such as that described in U.S. Pat. No. 4,655,766 of Theeuwes et al.Diffusional delivery devices known to the art however, do not possessthis capability.

The devices of this invention are particularly useful in providing apredetermined delayed onset of therapeutic effect for any desired timeperiod after application to the skin. Thus a device could be removed anda new one applied simultaneously, wherein the desired drug-free intervalis obtained.

One of the advantages of a continuous release dosage form, such as atransdermal drug delivery device, is the improvement in patientcompliance that is obtained from the concurrent removal of one deviceand application of a new device at the same time. This advantage is lostwhen removal and application occur at different times or where onset ofa therapeutic effect is desired at an inconvenient time such as shortlyprior to arousal from sleep. It is not possible, using concurrentapplication and removal of diffusional delivery devices known in theart, to substantially delay the onset of transdermal drug delivery fromthe time of application, such as bedtime, until shortly prior toarousal.

Additionally, a common problem encountered with state of the art systemsis how to deal with unstable active agents, especially those that tendto degrade the adhesive and other system components. Therefore, there isa continuing need for a transdermal therapeutic system that providesstability of the adhesive and all components during storage.

SUMMARY OF THE INVENTION

An object of this invention is to provide a diffusional drug deliverydevice which provides for delayed onset of drug administration.

A further object of this invention is to provide a diffusional drugdelivery device which does not deliver an initial burst of drug andhence is less likely to cause irritation.

Another object of this invention is to stabilize an active drug bystoring it within a transdermal therapeutic system, in form suitable forstorage.

A further object of this invention is to provide a diffusional deliverydevice where the adhesive and other components are protected fromdegradation by using a drug which in a first form is suitable forstorage, said form being more compatible with the system components uponprolonged exposure.

A further object of this invention is to provide for the maintenance ofdrug potency and device efficacy during prolonged storage periods,whereby the device is inactive while stored, and active when applied tothe skin.

A still further object of this invention is to provide a diffusionaldelivery device which continuously releases drug into a biologicalenvironment after a period of no drug delivery.

These and other objects, features, and advantages have been demonstratedby the present invention wherein a controlled release medical device forthe delivery of at least one therapeutic agent in a pre-determineddelivery rate pattern to a biological environment is comprised of, incombination: reservoir means containing a therapeutic agent which in afirst form is suitable for storage and which in a second form issuitable for absorption through the skin or mucosa by reaction with asolution formed by an activating agent and moisture available from thebody, the reservoir means having a surface substantially impermeable totherapeutic agent in its first form and permeable to therapeutic agentin its second form, through which the second skin absorbable form oftherapeutic agent is released to the biological environment; andactivating means containing an activating agent wherein said activatingagent in a first state is anhydrous and in a second state is in solutionwith moisture supplied by the body; whereby the therapeutic agent ischanged from its first to its second form by the activating means in itssecond state and whereby the passage of therapeutic agent to thebiological environment by diffusion is impeded until the agent changesforms.

BRIEF DESCRIPTION OF THE DRAWING

In the drawings, which are not drawn to scale, but rather are set forthto illustrate the various embodiments of the invention and wherein likereference numerals designate like parts, the drawings are as follows:

FIGS. 1, 2 and 3 are schematic cross-sectional views of embodiments ofthe transdermal drug delivery system of this invention, where the drugin a storage suitable form and the activating agent in its first stateare in separate reservoirs;

FIGS. 4, 5 and 6 are schematic cross-sectional views of embodiments ofthe transdermal drug delivery system of this invention, where the drugin a storage suitable form and the activating agent in its first stateare in the same reservoir;

FIG. 7 is a schematic cross-sectional view of an embodiment of thetransdermal drug delivery system of this invention where the activatingagent in its second state is microencapsulated;

FIGS. 8 and 9 are schematic cross-sectional views of embodiments of thetransdermal drug delivery system of this invention, where the drug inits first state is in a non-aqueous medium; and

FIGS. 10 and 11 are graphs illustrating the release rate of nicotinefrom transdermal drug delivery systems according to this invention.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Therapeutic agents suitable for transdermal administration exist invarious forms, some of which are more suitable for storage and some ofwhich are more suitable for administration through skin or mucosa. Forexample, a therapeutic agent may exist in a free base form, a free acidform, a salt form, an ester form, a non-covalent complex or an ioniccomplex, as for example, agents may exist as the phosphates orglycinates as ion pairs.

Many therapeutic agents such as fluorouracil, barbitol, furosemide,albuterol, apomorphine, benzocaine, acetylsalicylic acid, scopolamine,clonidine, phenylpropanolamine, chlorpheniramine, pilocarpine andephedrine, for example, are extremely stable in the salt form, such asthe sodium, calcium and magnesium cation salts, and the hydrobromide,hydrochloride, maleate, nitrate and sulfate anion salts. These agents,however, may be readily absorbable through the skin only in either thefree base form, the free acid form or the ester form, for example. Inthe past, therefore, transdermal delivery devices storing the agent inthe form suitable for absorption through the skin could have anundesirably short storage life. Similarly those storing the agent in aform suitable for storage could have an undesirable low agent deliveryrate through skin.

According to this invention, a therapeutic agent delivery device isprovided in which the therapeutic agent is converted from the storagesuitable form to the delivery suitable or absorbable form after thedevice is placed into its environment of use in contact with the skin ormucosa as a result of moisture entering the device form the environmentof use.

Along with stabilizing an otherwise active compound (drug) by storing itwithin the system in a stable form suitable for storage, for example inits salt form, this invention has the advantage of protecting theadhesive and other system components from any adverse reactions that arelikely to occur upon prolonged exposure to the active drug, as would bethe case under storage conditions.

An additional advantage of the transdermal drug delivery system of thisinvention is the delayed drug delivery and control of the initial excessburst of drug. In this manner, a means for delayed onset is providedwhich gives a drug-free period in plasma during continuous applicationof a transdermal drug delivery system.

With reference to the Figures, the devices shown, represent for purposesof illustration, transdermal delivery devices because these are thepreferred embodiments of this invention. It must be recognized however,that this invention is applicable to delivery devices generally and innon-transdermal applications, certain components such as the adhesiveand backing layers can be omitted. A transdermal delivery deviceaccording to this invention may include an impermeable backing member, atherapeutic agent reservoir containing a first storage suitable form ofa therapeutic agent which is subsequently converted to a seconddeliverable form which is suitable for absorption through the skin ormucosa, and an anhydrous activating means which contains an acid or abase activating agent which forms a solution with moisture availablefrom the body and converts the first storage suitable form of the drugto the second deliverable form.

It is believed that this invention has utility in connection with thedelivery of drugs within the broad class normally delivered through bodysurfaces and membranes, including skin and mucosa. As used herein, theexpressions "drug" and "therapeutic agent" are used interchangeably andare intended to have their broadest interpretation as anytherapeutically active substance which is delivered to a living organismto produce a desired, usually beneficial, effect. In general, thisincludes therapeutic agents in all of the major therapeutic areasincluding, but not limited to those disclosed in U.S. Pat. Nos.3,598,122, 3,598,123, 4,286,592, 4,314,557, 4,379,454 and 4,568,343, allof which are incorporated herein by reference.

This invention has particular utility in connection with the delivery ofall sympathomimetic drugs (bronchodilators) including but not limited toterbutaline, salbutamol and ephedrine. These drugs are placed in asystem according to this invention in a storage suitable, preferablysalt form, such as terbutaline sulfate, salbutamol sulfate and ephedrinehydrochloride, respectively. Additionally, this invention is useful indelivering ergot alkaloids such as ergonovine and ergotamine, present ina storage suitable form as a salt such as ergonovine mesylate andergotamine tartrate. Both the sympathomimetrics and the ergot alkaloidsin their active forms, have a tendency to be unstable and so thisinvention is particularly suitable since it uses a storage suitable formof the drug such as a salt, thereby providing a stable system.

This invention also finds utility in connection with the delivery ofdrugs such as benztropine, nicotine and secoverine. These drugs in theiractive form, tend to degrade the components of the system, including theadhesive, upon prolonged exposure such as is the case under storageconditions. The storage suitable forms, in particular the salt forms, ofthese drugs however, do not adversely affect the system's components.Therefore, benztropine mesylate, nicotine tartrate and secoverinehydrochloride can be placed in the system of this invention, to providedelivery of their respective drugs.

As stated above, this invention also eliminates the initial burst ofdrug. This is particularly beneficial in delivering drugs that have atendency in large doses, to irritate the skin. These drugs includebenztropine, secoverine and nicotine, as noted above, along withbeta-blockers such as propranolol and timolol. Storage suitable forms ofthe latter two drugs are the salt forms propranolol hydrochloride andtimolol hydrochloride, respectively.

A diffusional delivery device, in its broadest sense, comprises at leastone reservoir means from which at least one therapeutic agent or drugpasses by diffusion to the agent releasing surface of the device andfrom there into the biological environment to which it is applied.

In the preferred embodiment of this invention, a therapeutic agent istransdermally administered to the skin or mucosa, said agent beingstored in the diffusional delivery device in a first form suitable forstorage, hereinafter referred to as the storage suitable form.Preferably, a salt form of an acid or a base drug is used. Typicalexamples include, without limitation, nicotine salt, secoverine salt andbenztropine salt. The therapeutic agent is converted during deliveryfrom its reservoir, into a second form which is suitable for absorptionthrough skin or mucosa, by reacting with the activating agent which isin solution with moisture supplied by the body, said second formhereinafter referred to as the deliverable form. While the therapeuticagent in its deliverable form is able to permeate the layers of thesystem and ultimately the skin itself, the storage suitable form of thetherapeutic agent can not. The inability of the therapeutic agent in itsfirst form to permeate the system and the skin ensures that thetherapeutic agent will remain within the reservoir until the onset ofdelivery is desired, at which time an activating means converts thetherapeutic agent to its deliverable form. Typically, the second ordeliverable form of the therapeutic agent is a free base form or a freeacid form.

In order that premature reaction be prevented, the therapeutic agent andthe activating agent are maintained in an anhydrous environment prior touse. Within these broad limitations, the specific structure of theadministration device is not critical to this invention. The therapeuticagent and the activating agent may be dispersed within an anhydrousmatrix, either as a solid, non-aqueous liquid or gel, or mixed withsuitable anhydrous carriers, permeation enhancers and the like as isknown in the art. The devices are preferably in the form of an adhesivepatch or the like but can also be in the form suitable for applicationto the skin or mucosa such as anhydrous ointment, gel or matrix, forexample. If desired, means for controlling the release rate can also beused, as is known in the art.

The delivery system of this invention can be used to provide delayeddelivery of more than one drug, if desired. If the drugs to be deliveredhave the same storage suitable form, for example, either the salt of abase drug or the salt of an acid drug, both drugs remain within thereservoir until the onset of delivery is desired, at which time they areconverted to their deliverable form by the activating means. Since thesedeliverable forms are suitable for absorption through skin, the drugsare co-delivered.

This invention can also be used to provide a system where a first drugis continuously delivered, said delivery commencing immediately uponplacement of the system on skin, and a second drug is delivered after apredetermined delay. This can be accomplished by utilizing a first drugwhich is a neutral or non-salt formable drug such as hydrocortisone,capable of permeating the layers of the system. The second drug is inthe storage suitable form, for example, the salt form of an acid or basedrug which can not permeate the layers in that form. Moisture from theskin activates the activating means which converts the second drug fromits storage form to its deliverable form. This conversion processcreates the delay between application of the system and onset ofdelivery of the second drug.

Alternately, this invention can provide a system that will deliver afirst drug and subsequently a second drug, and delivery of the firstdrug ceases when delivery of the second drug commences. The first drugcan be the free form of an acid drug and the second, the salt form of abase drug. Alternately, the first drug can be the free form of a basedrug and the second, the salt form of an acid drug. In either case, thesystem is permeable to the passage of drug in its free form andsubstantially impermeable to passage of drug in its salt form. When thesystem is placed upon the skin, delivery of the free form of the drugcommences. Meanwhile, moisture available from the body diffuses into theactivating means, converting the activating agent to its second stateand the activating agent now in solution migrates into the drugreservoir, converting the salt form of the second drug into its freeform and likewise converting the free form of the first drug into itssalt form. Thus, delivery of the second drug, now in its free form,commences and since the first drug is now in its salt form and thereforeimpermeable, its delivery ceases.

This invention can provide delayed delivery in a variety of embodiments,which are best described with relation to the Figures. FIGS. 1, 2, and 3illustrate embodiments of the invention which have the reservoir meansseparate from the activating means. The simplest of these is shown inFIG. 1. System 10 is comprised of drug reservoir means 12 and activatingmeans 14. The system is also provided with an impermeable backing layer16, an in-line pharmaceutically acceptable contact adhesive 18 and astrippable release liner 20, which is removed prior to application tothe skin. The various layers are laminated or otherwise assembled into abandage having a predetermined size and shape as is known to the art.

The drug reservoir 12 is in the form of a matrix or carrier having astorage suitable form of the drug to be delivered, dispersed throughout.The system components are substantially impermeable to the passage ofthe storage suitable form of the drug but permeable to the second formof the drug, which is suitable for absorption through the skin ormucosa.

Activating means 14 is a layer comprised of an anhydrous activatingagent which can be either an acid or a base dispersed in a matrix orcarrier. Suitable acids include without limitation, citric acid,succinic acid, oxalic acid, succinic anhydride, phthalic acid, phthalicanhydride, sodium bisulfate and salicylic acid. Likewise, suitable basesinclude without limitation, Na₂ CO₃, NaHCO₃, K₃ CO₃, KHCO₃, Na₃ PO₄, Na₂HPO₄, sodium oxalate, sodium succinate, sodium citrate, sodiumsalicylate, and all other salts of organic acids.

When the system 10 is first placed on the patient's skin, the system- orskin-impermeable storage suitable form of the drug in reservoir 12 issequestrated from the activating means 14 and reservoir 12 issubstantially free of activating agent. Likewise, the activating means14 is substantially free of drug, both the storage suitable and thedeliverable form. This is due to the fact that in an anhydrousenvironment such as is the case at storage conditions, the drug in itsfirst form, in reservoir 12 and the activating agent in activating means14 are for the most part, non-reactive.

In accordance with a preferred embodiment of the invention, theactivating means 14 is activated by moisture, which is readily availablefrom the site of administration such as the cutaneous surface,particularly in occluded regions. Means 14 may alternatively bemoistened by dipping into a liquid containing vessel immediately priorto application. In operation, this moisture migrates into the system 10from the skin surface or other source, typically by osmosis ordiffusion, passing through the adhesive layer 18 and then to theactivating means 14 where it mixes with the acid or base containedtherein. The acid or base forms an acidic or basic solution and migratesinto the salt drug layer, reacting with the salt drug to convert it intoits free form which then passes freely through layers 14 and 18 and thenthrough the skin.

The drug releasing surfaces of certain embodiments of our invention arecharacterized by being substantially free of drug at the time they areapplied to the body. As used herein, the expression "substantially freeof drug" means either free of drug or containing an amount of druginsufficient to establish untoward effects on skin (eg. irritation) orto establish and maintain therapeutically effective drug delivery ratesat the time of application to the delivery site. In this manner, theadhesive layer 18 is substantially free of drug.

FIG. 2 illustrates another embodiment of the invention where thelaminated system 22 is provided with a rate controlling membrane 24positioned between the drug reservoir 12 and the activating means 14.Membrane 24 controls the rate at which activating agent diffuses frommeans 14 into reservoir 12. Therefore, the rate at which the storagesuitable form of the drug is converted and subsequently delivered, isalso controlled, indirectly.

Membrane 24 is fabricated of a material such that it is substantiallyimpermeable to the passage of the first form of the drug and to thecontents of layer 12, and substantially permeable to the passage of theactivating agent in solution with water or other biological fluid, andalso permeable to drug in its second form. This rate controllingmembrane may be fabricated from permeable, semipermeable or microporousmaterials which are known in the art to control the rate of agentsand/or fluids into and out of delivery devices. It is preferable thatthe in vitro flux of agent in solution across membrane 24 is less thanthe rate (per cm²) that said agent goes into solution. However, thisinvention also contemplates use of a membrane having an in vitro fluxgreater than or equal to that rare that agent goes into solution.

FIG. 3 illustrates an embodiment similar in construction to that of FIG.2. Laminated system 26 also has a rate controlling membrane 28. However,in system 26, the membrane 28 is interposed between the activating means14 and the adhesive 18. In this embodiment, the membrane 28 controls therate at which moisture enters the system, and therefore the rate atwhich the activating means 14 becomes hydrated.

Membrane 28 is fabricated from a material such that it is substantiallyimpermeable to the passage of the activating agent and other componentsof activating means 14, and substantially permeable to the passage ofdrug in its second form. The membrane is preferably of a material suchthat the in vitro flux of moisture across membrane 28 is less than thein vitro flux of moisture through the skin.

FIGS. 4, 5 and 6 illustrate embodiments of the invention where the drugreservoir and the activating means are combined, ie. there is a singlereservoir containing both the drug in its storage suitable form and theactivating agent.

In FIG. 4, system 30 is comprised of a reservoir 32 and a ratecontrolling membrane 34. Membrane 34 controls the rate at which moistureenters reservoir 32. The reservoir 32 is formed by dry blending the drugin its first form, and an activating agent, without any carrier vehicleor nonaqueous vehicle. The first form of the drug can not permeatemembrane 34 until moisture is available from the skin or other source.When moisture becomes available, it passes through membrane 34 and intothe reservoir 32 where the activating agent becomes hydrated andconverts the first form to the second form of the drug, which then canpass through membrane 34 and adhesive 18. Backing member 16, instead ofbeing flat, forms an envelope or pouch in which the reservoir 32 isheld. This configuration is especially suitable for use when thereservoir 32 is not self-supporting.

FIG. 5 illustrates a laminated system 36 having a single reservoir 38where the drug in its first form and the activating agent are dispersedthroughout a matrix or carrier. In FIG. 6, laminated system 40 has arate controlling membrane 34 positioned between the drug/agent reservoir38 and the adhesive 18.

The embodiments of FIGS. 1-6 rely on external moisture to activate thesystem, whereby moisture from the skin forms an aqueous solution withthe activating agent which can then convert the drug from its firststorage suitable form into its second deliverable form. FIG. 7 providesa system where the activating agent in an aqueous solution is actuallyplaced into the system 42, thereby avoiding the need for an externalsource of moisture.

System 42 is comprised of an agent reservoir 44 where an aqueoussolution of activating agent is microencapsulated in wax. Thesemicrocapsules 46 can be broken and the solution released uponapplication of pressure or they can be melted and the solution releasedupon application of heat. The activating solution then migrates throughthe microporous membrane 48 and into the drug reservoir 12 where thedrug in its first form is converted to the second absorbable form of thedrug, which is then delivered to the skin.

Microporous membrane 48 may be formed from polymers such aspolypropylene, polytetrafluorethylene, polycarbonates,polyvinylchloride, cellulose acetate, cellulose nitrate andpolyacrylonitrile, for example.

The embodiments of FIGS. 8 and 9 illustrate placement of the storagesuitable form of the drug in a non-aqueous medium as compared to apolymeric matrix. Suitable materials for the non-aqueous medium include,without limitation, mineral oil, silicone oil and petrolatum.

FIG. 8 shows system 50 having the drug/non-aqueous medium in reservoir52. The system 54 of FIG. 9 has the same reservoir but additionally hasa microporous membrane 48 interposed between reservoir 52 and theactivating agent reservoir 14.

FIG. 10 is a graphical representation of the theoretical release rateprofile versus time for the system illustrated in FIG. 3. The system 26would be positioned on the skin at time zero. From time zero until timet, moisture from the skin would diffuse through the rate controllingmembrane 28, into the activating layer 14 and acid or base in solutionwould migrate into the drug layer 12 to convert the drug in its firstform to its second absorbable form, which subsequently would diffusethrough the layers to reach the skin surface. Shortly after time t, thedrug would begin to actually be delivered into the bloodstream. This isindicated by the rise on the curve in FIG. 10.

The delay time (time zero until time t) depends upon both the watermigration through the rate controlling membrane 28 and the activatinglayer 14.

Various materials suited for the fabrication of the various layers aredisclosed in the aforementioned patents. The polymer matrix of the drugreservoir 12, the activating agent reservoir 14, and combined reservoir38, are anhydrous and suitable materials include without limitation,natural and synthetic rubbers or other polymeric materials, thickenedmineral oil or petroleum jelly. The preferred embodiment according tothis invention is fabricated from an ethylene/vinylacetate (EVA)copolymer of the type described in U.S. Pat. No. 4,144,317, preferablythose having a vinylacetate content in the range of about 18 to 60weight percent. Particularly good results have been obtained using anEVA copolymer of about 40 weight percent vinylacetate content (40 w%VA). The drug and/or agent is preferably dispersed through the matrix ata concentration in excess of saturation, the amount of the excess beinga function of the intended useful life of the system.

In addition to the drug and/or agent, the matrix may also contain othermaterials such as dyes, pigments, inert fillers, permeation enhancers,excipients and conventional components of pharmaceutical products ortransdermal therapeutic systems as is known to the art. The drug and/orthe activating agent containing matrices may also contain a salt such asNaCl, which facilitates the onset of drug delivery by osmoticallydrawing up moisture from the skin.

One face surface of the drug reservoir bears a backing member 16. Thepurpose of the backing is to prevent passage of the drug through thesurface of the reservoir distant from the adhesive layer. An ancillarypurpose of the backing is to provide support for the system, whereneeded. The backing layer can be flexible or nonflexible and suitablematerials include without limitation, cellophane, cellulose acetate,ethylcellulose, plasticized vinylacetate-vinylchloride copolymers,polyethylene terephthalate, nylon, polyethylene, polypropylene,metalized polyester films, polyvinylidene chloride, coated flexiblefibrous backings such as paper and cloth and aluminum foil. Suchbackings can be in the form of precast films or fabrics which are bondedto the reservoir by heat or adhesives and can be coated onto thereservoir. Numerous other suitable materials are disclosed in U.S. Pat.No. 4,661,105, incorporated herein by reference.

The composition and thickness of adhesive layer 18 are such that layer18 does not constitute a significant permeation barrier to the passageof drug. Adhesive layer 18 may also contain a predetermined amount ofthe skin absorbable form of the drug which serves to saturate the skinfor more rapid therapeutic effects where desired. Silicone compounds arecommonly used as adhesives, however numerous materials are known whichpossess the requisite strength and skin compatibility. An adhesiveoverlay or other means for maintaining the device on the skin can beemployed instead of, or in combination with, adhesive lamina 18.Suitable adhesive materials are noted in the aforementioned patent.

In operation, linear 20 is removed and the system is placed in directcontact with the skin. The releaseable liner is made from materialswhich are substantially impermeable to the drug, and any othercomponents of the layers. The same materials that are used to make thebacking layer may be used to make the liner, provided they are madestrippable such as by siliconizing.

The aforementioned patents describe a wide variety of materials whichcan be used for fabricating the various layers of the transdermaldelivery systems according to this invention. This invention thereforecontemplates the use of materials other than those specificallydisclosed herein, including those which may hereafter become known tothe art to be capable of performing the necessary functions.

EXAMPLE I

A test sample was designed to deliver nicotine according to thisinvention. Nicotine which is transdermally administered to facilitatebreaking the tobacco habit, is especially suited to illustrate thisinvention. Nicotine in its active form tends to degrade adhesives,especially those which are silicone based. Also, nicotine delivered in asudden burst may irritate the skin. Therefore, use of this invention todeliver nicotine provides a system with an improved shelf-life bystoring the nicotine in its salt form, and further provides eliminationof the initial burst of drug by storing nicotine in a form which is notreadily absorbed through mucous membrane and intact skin.

The drug reservoir was a polymeric matrix comprised of 60% nicotinetartrate and 40% EVA 40 carrier, and was about 6.5 mils thick. Theactivating layer was about 3.5 mils thick and was a polymeric matrixcomprised of 60% Na₂ CO₃ and 40% EVA 40 carrier. Sodium carbonateprovides an aqueous solution which is strongly alkaline. Thus, in thisparticular embodiment, the activating layer was a base.

The release rate was measured at 35° C. using a 1.5 mil Hytrel® (DuPont) membrane, which simulates water diffusion through human skin. Therelease rate profile is illustrated in FIG. 10.

Prior to application to the Hytrel® membrane, the activating layer isanhydrous and therefore inert and is substantially impermeable to thepassage of drug and is thus substantially free of drug, both nicotineand nicotine tartrate. When the system is placed in contact with theHytrel® membrane, moisture migrates through the membrane and into theactivating layer which then becomes hydrated and active.

Moisture entering the EVA polymeric matrix reacts with the solid Na₂ CO₃to form a basic solution. Thus, the activating agent undergoes a changeof state from a first anhydrous and inert state to a second hydrated andactive state, where the activating agent is in solution.

The basic solution then diffuses through the activating matrix and intothe drug reservoir, where it reacts with the solid nicotine tartrate toconvert it to its free form, nicotine. The agent nicotine then passesfreely through the activating layer and then through the Hytrel®membrane. The activating layer in its dry state is impermeable to thepassage of nicotine tartrate but in its hydrated state, is permeable tothe passage of nicotine.

EXAMPLE II

A system was designed according to this invention and is illustrated inFIG. 7. The backing was standard Medpar® and the system had the storagesuitable form of the drug and the activating agent (base) mixed in thesame reservoir. The drug reservoir was comprised of 42% nicotinetartrate, 18% Na₂ CO₃ and 40% EVA 40 carrier. The system had a PVA ratecontrolling membrane about 1.5 mils thick and had a silicone adhesivelayer.

The release rate of nicotine from this system at 35° C. in a releasemedium of water, is presented in the following table:

                  TABLE I                                                         ______________________________________                                        Time, hrs Average Release Rate, μg/cm.sup.2 /hr                            ______________________________________                                        2         72.64                                                               4         29.55                                                               6         45.84                                                               8         52.60                                                               13        112.51                                                              ______________________________________                                    

As is evidenced from the data presented, this system provides thedesired delayed onset where the drug release rate during the first 8hours is minimal and gradually increases to a significant level at 13hours.

EXAMPLE III

A test sample was designed to deliver nicotine. The drug reservoir was apolymeric matrix comprised of 40% nicotine tartrate, 50% EVA 40 carrierand 10% NaCl, and was about 8 mils thick. The activating layer was about3.5 mils thick and was a polymeric matrix comprised of 60% Na₂ CO₃ and40% EVA 40 carrier.

The release rate was measured using a 1.5 mil Hytrel® membrane and isgraphically illustrated in FIG. 11.

Having thus generally described our invention and described in detailcertain preferred embodiments thereof, it will be readily apparent thatvarious modifications to the invention may be made by workers skilled inthe art without departing from the scope of this invention which islimited only by the following claims.

What is claimed is:
 1. A controlled release medical device for deliveryof at least one therapeutic agent in a pre-determined delivery ratepattern to a biological environment comprising, in combination:reservoirmeans containing a therapeutic agent which in a first form is suitablefor storage and in a second form in suitable for absorption through theskin or mucosa, and said reservoir means having a surface substantiallyimpermeable to said therapeutic agent in said first form and permeableto said therapeutic agent in said second form and through which thesecond form of said therapeutic agent is released to the biologicalenvironment; and activating means containing a plurality ofmicrocapsules containing an activating solution; whereby the therapeuticagent is changed from its first to its second form by release of theactivating solution from said microcapsules, and whereby the passage oftherapeutic agent to the biological environment by diffusion is impededuntil the therapeutic agent changes form.
 2. The device of claim 1wherein said reservoir means is a matrix having a therapeutic agentdispersed throughout, said means being substantially free of activatingagent.
 3. The device of claim 1 wherein said microcapsules arebreakable.
 4. The device of claim 1 wherein said microcapsules aremeltable.
 5. The device of claim 1 which further comprises:ratecontrolling means for controlling the rate at which activating agent,once released from the microcapsules, diffuses into said reservoirmeans.
 6. The device of claim 1 wherein said therapeutic agent isselected from the group consisting of fluorouracil, barbitol,furosemide, albuterol, apomorphine, benzocaine, acetylsalicylic acid,scopolamine, clonidine, phenylpropanolamine, chlorpheniramine,pilocarpine, terbutaline, salbutamol, ephedrine, ergonovine, ergotamine,benzotropine, nicotine, secoverine, propranolol and timolol.
 7. Acontrolled release medical device for delivery of nicotine in apre-determined delivery rate pattern to a biological environmentcomprising, in combination:reservoir means containing nicotine tartratewhich is a form of nicotine suitable for storage, said nicotine tartratebeing subsequently changed to nicotine which is suitable for absorptionthrough the skin or mucosa, and said reservoir means having a surfacesubstantially impermeable to nicotine tartrate and permeable to nicotineand through which nicotine is released to the biological environment;and activating means containing a plurality of microcapsules containingan activating solution; whereby nicotine tartrate is changed to nicotineby release of the activating solution from said microcapsules, andwhereby the passage of nicotine to the biological environment bydiffusion is impeded until the nicotine tartrate changed form.